Viruses are subcellular agents that rely on the molecular machinery of a host cell to replicate. They have evolved to infect almost every organism and are increasingly being employed in scientific research. Although viruses contain very small genomes encoding only a few necessary proteins, they have adapted to evade immune systems and transmit efficiently from host to host. (See, e.g., Fields, B. N., et al., Fields Virology, 5th edit, 2007; and Strauss, J. H. & Strauss, E. G., Viruses and Human Disease, 2nd edit, 2008, the disclosures of which are incorporated herein by reference.)
Viruses come in different shapes, sizes, and types of genomic information, one such sub-type are the “enveloped viruses”. Enveloped viruses are a class of viruses that bud from the plasma or internal membrane of plants or animals during their replication. The newly budded viral particle contains the genomic material inside a protein capsid, which in turn is surrounded by membrane from the host and envelope proteins. Envelope proteins are often heavily glycosylated by the host machinery, and therefore are often not immediately recognized by the immune system. These envelope glycoproteins are usually involved in interactions with cellular receptors on target host cells, triggering membrane fusion and infection.
Enveloped viruses cause many well known diseases, including influenza, Ebola, chicken pox, SARS (severe acute respiratory syndrome), small pox, and AIDS. (See, e.g., Fields, et al., cited above.) Human immunodeficiency virus (HIV), the virus that causes AIDS, affects approximately 33 million people throughout the world and causes approximately 2 million HIV-related deaths per year. (See, e.g., UNAIDS, Report On The Global AIDS Epidemic, 2008, the disclosure of which is incorporated herein by reference.) While current retroviral therapies have extended the length and quality of life of those infected with HIV, resistant strains are becoming increasingly common, and additional treatments and a broad spectrum vaccine are necessary to prevent additional infections. In turn, although influenza does not typically cause the mortality of HIV, it is a highly contagious virus that can be lethal, usually in the very young and very old, and in those with immune deficiencies. Moreover, influenza pandemics, such as the one in 1918 when an estimated 40 million people worldwide were killed, are capable of causing a significant number of deaths, including in healthy young adults. (See, e.g., Reid, A. H., et al., J Gen Virol, 84, 2285-92, 2003, the disclosure of which is incorporated herein by reference.)
Current treatment for viral infection varies widely for different viruses. Effective vaccines are available for smallpox, measles, hepatitis, and varicella-zoster (chicken pox) viruses, among others. However, there are significant limitations to current vaccines. For example, influenza vaccines are typically effective against the strains included in the vaccine, but must be readministered every year due to the rapid mutation rate of the virus. (See, e.g., Mossad, S. B. Cleve Clin J Med, 74, 889-94, 2007, the disclosure of which is incorporated herein by reference.) Moreover, for some enveloped viruses there is no vaccine and therefore treatment of the infection is the primary clinical goal. For example, there are currently no vaccines available for Ebola virus, herpes viruses, hanta viruses, HIV, and many other potentially deadly viruses. For many of these diseases, treatment is administered to make the patient more comfortable, provide symptom relief, or decrease the viral load to allow the immune system to more easily fight off the infection. (See, e.g., Enserink, M., Science, 302, 1141-2, 2003 and Emmert, D. H., Am Fam Physician, 61, 1697-706, 1708, 2000, the disclosures of which are incorporated herein by reference.)
Efforts to develop a vaccine for HIV have met with limited success, with promising laboratory results thus far leading only to failures in clinical trials. (See, e.g., Burton, D. R., et al., Nat Immunol, 5, 233-6, 2004; Karlsson Hedestam, G. B., et al., Nat Rev Microbiol, 6, 143-55, 2008; Endsley, A. N., et al., Curr HIV Res, 6, 401-10, 2008; Burton, D. R., et al., Proc Natl Acad Sci USA, 102, 14943-8, 2005; Cardoso, R. M., et al., Immunity, 22, 163-73, 2005; Trkola, A., et al., J Virol, 70, 1100-8, 1996; and Burton, D. R., et al., Science, 266, 1024-7, 1994, the disclosures of each of which are incorporated herein by reference.)
While research continues on developing an effective and cross-reactive vaccine, patients currently rely on antiviral drugs to decrease their viral load and prolong their lives. HIV antiviral therapy usually consists of three or more antiretroviral drugs from at least two inhibitory classes in a therapeutic regimen known as highly active antiretroviral therapy (HAART). (See, e.g., Endsley, A. N., et al., 2008, cited above.) As of 2008, 32 antivirals have been approved by the FDA for treatment of HIV-1 infections. Although HAART has been quite successful at reducing the viral load of patients, the rapid mutation rate of HIV often eventually leads to drug resistant strains, rendering antiviral treatment ineffective. (See, e.g., Shafer, R. W. & Schapiro, J. M., AIDS Rev 10, 67-84, 2008, the disclosure of which is incorporate herein by reference.)
Unlike for HIV, there is a very effective vaccine for influenza. However, the inconvenience and cost of yearly immunization, as well as the unpredictable mutation of influenza, means that millions of people are susceptible to infection every year. (See, e.g., Tosh, P. K., et al., Mayo Clin Proc, 83, 77-84, 2008; and Weingarten, S., et al., Am J Infect Control, 17, 202-7, 1989.) In addition, the recent emergence of a highly lethal H5N1 strain (“bird flu”), and concerns over the recent outbreak of H1N1 (“swine flu”), has led to concerns that these strains could become easily transmittable from human to human or weaponized, creating a massive influenza pandemic. (See, e.g., Webby, R. J. & Webster, R. G., Science, 302, 1519-22, 2003; von Itzstein, M., Curr Opin Chem Biol, 12, 102-8, 2008; Ong, A., et al., Ann Acad Med Singapore, 37, 477-81, 2008; and Krug, R. M. Antiviral Res, 57, 147-50, 2003, the disclosures of each of which are incorporated herein by reference.) Although Influenza A, including H5N1 strains, can be treated with antiviral medications, including oseltamivir (Tamiflu) and zanamivir (Relenza), resistance to oseltamivir and other common influenza antivirals have already been reported in H5N1 cases. (See, e.g., Sugrue, R. J., et al., Ann Acad Med Singapore, 37, 518-24, 2008; Proenca-Modena, J. L., et al., Braz J Infect Dis, 11, 125-33; de Jong, M. D., et al., N Engl J Med, 353, 2667-72, 2005; Le, Q. M., et al., Nature, 437, 1108, 2005; He, G., et al., Antiviral Res, 77, 72-6, 2008; and Cheung, C. L., et al., Infect Dis, 193, 1626-9, 2006, the disclosures of each of which are incorporated herein by reference.)
As described above, traditional approaches for preventing and treating viral infection largely rely on vaccination and small molecule anti-viral drug treatment, respectively. Whether induced by vaccination, natural infection, or directly injected, antibodies that leverage the natural host immune system provide a powerful countermeasure to viral infection. Unfortunately, by its very nature the immune system relies on highly specific interactions with the antigen, which can be defeated by escape mutations that either arise naturally in the viral population or that are engineered. Similarly, escape mutations can render ineffective the beneficial action of anti-viral medications.
However, enveloped viruses by their nature contain structures that may provide a new therapeutic target. Specifically, enveloped viruses commonly contain glycosylated envelope proteins that can function in host cell recognition as well as in host immune system evasion by protecting otherwise antigenic protein sites via glycosylation. It has been recently recognized that reagents (such as lectins), that target the carbohydrate portion of glycoproteins, have the potential to neutralize viral infection by blocking binding interactions required for target cell recognition. (See, e.g., Balzarini, J., Nature Reviews Microbiology, 5: 583-597, 2007, the disclosure of which is incorporated herein by reference.) Importantly, such reagents have the potential to drive viral evolution toward lower glycosylation levels, which could expose hidden antigenic regions that will then be subject to antibody-based immune action. (See, Smee D. F., et al., Antivirial Chemistry and Chemotherapy, 18: 317-327, 2008, the disclosure of which is incorporated herein by reference.) However, to date no therapeutically successful agents targeted at the envelope regions of these viruses have been developed.
In summary, although treatment options of variable effectiveness are available for many envelope type viruses, a need exists for new and improved small molecule and protein-based therapeutics that limit the development of drug resistant strains. Such therapeutics, along with the creation of effective vaccines, will greatly improve the outlook for currently infected patients as well as being beneficial in the case of a pandemic, especially for medical personnel and first-line defenders.